Splicing of an automodulatory domain in Ca(v)1.4 Ca(2+) channels confers distinct regulation by calmodulin

Ca(2+) influx through Ca(v)1.4 L-type Ca(2+) channels supports the sustained release of glutamate from photoreceptor synaptic terminals in darkness, a process that is critical for vision. Consistent with this role, Ca(v)1.4 exhibits weak Ca(2+)-dependent inactivation (CDI)—a negative feedback regulation mediated by Ca(2+)-bound calmodulin (CaM). CaM binds to a conserved IQ domain in the proximal C-terminal domain of Ca(v) channels, but in Ca(v)1.4, a C-terminal modulatory domain (CTM) disrupts interactions with CaM. Exon 47 encodes a portion of the CTM and is deleted in a Ca(v)1.4 splice variant (Ca(v)1.4Δex47) that is highly expressed in the human retina. Ca(v)1.4Δex47 exhibits CDI and enhanced voltage-dependent activation, similar to that caused by a mutation that is associated with congenital stationary night blindness type 2, in which the CTM is deleted (K1591X). The presence of CDI and very negative activation thresholds in a naturally occurring variant of Ca(v)1.4 are perplexing considering that these properties are expected to be maladaptive for visual signaling and result in night blindness in the case of K1591X. Here we show that Ca(v)1.4Δex47 and K1591X exhibit fundamental differences in their regulation by CaM. In Ca(v)1.4Δex47, CDI requires both the N-terminal (N lobe) and C-terminal (C lobe) lobes of CaM to bind Ca(2+), whereas CDI in K1591X is driven mainly by Ca(2+) binding to the C lobe. Moreover, the CaM N lobe causes a Ca(2+)-dependent enhancement of activation of Ca(v)1.4Δex47 but not K1591X. We conclude that the residual CTM in Ca(v)1.4Δex47 enables a form of CaM N lobe regulation of activation and CDI that is absent in K1591X. Interaction with the N lobe of CaM, which is more sensitive to global elevations in cytosolic Ca(2+) than the C lobe, may allow Ca(v)1.4Δex47 to be modulated by a wider range of synaptic Ca(2+) concentrations than K1591X; this may distinguish the normal physiological function of Ca(v)1.4Δex47 from the pathological consequences of K1591X.